Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer

Stem Cells. 2016 Nov;34(11):2613-2624. doi: 10.1002/stem.2447. Epub 2016 Jul 11.


The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.

Keywords: Cancer stem cells; Liver cancer; OCT4; Pluripotency; Positive feedback; Reprogramming; c-JUN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Differentiation
  • Cellular Reprogramming
  • Cisplatin / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Feedback, Physiological*
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • JNK Mitogen-Activated Protein Kinases / genetics*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / genetics*
  • Octamer Transcription Factor-3 / metabolism
  • Signal Transduction
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcriptional Activation
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Doxorubicin
  • JNK Mitogen-Activated Protein Kinases
  • Cisplatin
  • Fluorouracil